Human Molecular Genetics, 2008, Vol. 17, No. 17 2595–2609 doi:10.1093/hmg/ddn159 Advance Access published on May 23, 2008 Sex differences in a transgenic rat model of Huntington’s disease: decreased 17b-estradiol levels correlate with reduced numbers of DARPP321 neurons in males
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Felix J. Bode , Michael Stephan , Hendrik Suhling , Reinhard Pabst , Rainer H. Straub , Downloaded from https://academic.oup.com/hmg/article-abstract/17/17/2595/632381 by guest on 27 June 2020 Kerstin A. Raber3, Michael Bonin4, Huu Phuc Nguyen4, Olaf Riess4, Andreas Bauer5,6, Charlotte Sjoberg7,A˚ sa Peterse´n7 and Stephan von Ho¨ rsten1,3,
1Institute of Functional and Applied Anatomy, Medical School of Hannover, 30625 Hannover, Germany, 2Department of Internal Medicine I, University Regensburg, 93042 Regensburg, Germany, 3Experimental Therapy, Franz-Penzoldt- Center, Friedrich-Alexander-University Erlangen-Nu¨rnberg, 91054 Erlangen, Germany, 4Department of Medical Genetics, University of Tu¨bingen, 72076 Tu¨bingen, Germany, 5Institute of Neurosciences and Biophysics, Research Centre Juelich, 52425 Juelich, Germany, 6Department of Neurology, Heinrich-Heine University Duesseldorf, 40001 Duesseldorf, Germany and 7Translational Neuroendocrine Research Unit, Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden
Received March 10, 2008; Revised May 8, 2008; Accepted May 21, 2008
Recent clinical studies have highlighted that female sex hormones represent potential neuroprotective mediators against damage caused by acute and chronic brain diseases. This evidence has been confirmed by experimental studies documenting the protective role of female sex hormones both in vitro and in vivo, although these studies did not specifically focus on Huntington’s disease (HD). We therefore investigated the onset and course of HD in female and male transgenic (tg) HD (CAGn51) and control rats across age and focused on three aspects: (i) behavioral and physiological alterations (energy expenditure, home-cage activity, emotional disturbance and motor dysfunction), (ii) morphological markers (numbers and characteristics of striatal DARPP321 medium-sized spiny neurons (MSNs) and dopamine receptor autoradiography) and (iii) per- ipheral sex hormone levels as well as striatal estrogen receptor expression. Independent of their sex, tgHD rats exhibited increased levels of food intake, elevated home-cage activity scores and anxiolytic-like behavior, whereas only males showed an impairment of motor function. In line with the latter finding, loss and atrophy of DARPP321 MSNs were apparent only in male tgHD rats. This result was associated with a decreased striatal dopamine D1 receptor density and lower plasma levels of 17b-estradiol at the age of 14 months. As DARPP321 MSNs expressed both a-andb-estrogen receptors and showed a correlation between cell numbers and 17b-estradiol levels, our findings suggest sex-related differences in the HD phenotype pointing to a substantial neuroprotective effect of sex hormones and opening new perspectives on the therapy of HD.
INTRODUCTION striatal neurodegeneration (2). The clinical triad of motor dys- function, cognitive decline and psychiatric manifestations Huntington’s disease (HD) is a polyglutamine disorder based on characterizes HD. Owing to its autosomal-dominant inheri- an expanded CAG triplet repeat (1) leading to cerebral and tance, the prevalence is equally distributed between both